This invention relates to novel tetrahydroisoquinoline compounds that are useful as estrogen agonists and antagonists, and the pharmaceutical uses thereof.
The value of naturally occurring estrogens and synthetic compositions demonstrating xe2x80x9cestrogenicxe2x80x9d activity has typically been in their medical and therapeutic uses. A traditional listing of the therapeutic applications for estrogens alone or in combination with other active agents includes, but is not limited to, oral contraception, relief for the symptoms of menopause, prevention of threatened or habitual abortion, relief of dysmenorrhea, relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne, diminution of excessive growth of body hair in women (hirsutism), the prevention of cardiovascular disease, treatment of osteoporosis, treatment of prostatic carcinoma, and suppression of postpartum lactation (Goodman and Gilman, The Pharmacological Basis Of Therapeutics (7th Ed.), Macmillan Publishing Company, 1985, pages 1421-1423). Accordingly, there has been increasing interest in finding newly synthesized compounds and new uses for previously known compounds that are demonstrably estrogenic, that is, able to mimic the action of estrogen in estrogen responsive tissue.
From the viewpoint of pharmacologists interested in developing new drugs useful for the treatment of human diseases and specific pathological conditions, it is desirable to procure compounds having demonstrable estrogen-like function, but which are devoid of unwanted side-effects. Exemplifying this latter view, osteoporosis, a disease in which bone becomes increasingly more fragile, is greatly ameliorated by the use of fully active estrogens. However, due to the recognized increased risk of uterine cancer in patients treated chronically with active estrogens, it is not clinically advisable to treat osteoporosis in intact women with fully active estrogens for prolonged periods.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more that 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip, and 240,000 wrist fractures annually. These injuries cost the nation over $10 billion per year. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of the survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase 3-fold over the next 60 years, and one study estimates there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle, and low calcium intake.
Estrogen is the agent of choice in preventing osteoporosis or post menopausal bone loss in women; it is the only treatment that unequivocally reduces fractures. However, estrogen stimulates the uterus and is associated with an increased risk of endometrial cancer. Although the risk of endometrial cancer is thought to be reduced by a concurrent use of a progestogen, there remains concern about possible increased risk of breast cancer with the use of estrogen.
Black et al., in EP 0605193A1, report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises plasma levels of the beneficial high density lipoproteins (HDLs). Thus, estrogen can be an effective therapy for hypercholesterolemia. However, as discussed supra, long-term estrogen therapy has been implicated in a variety of disorders, including an increase in the risk of uterine and breast cancer, causing many women to avoid this treatment. Recently suggested therapeutic regimens, that seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, cause the patient to experience unacceptable bleeding. Furthermore, combining progestogen with estrogen seems to blunt the desired serum cholesterol effects of estrogen. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for hypercholesterolemia that have the desirable effect on serum LDL but do not cause undesirable effects.
There is a need for improved estrogen agonists that exert selective effects on different tissues in the body. Tamoxifen, or 1-(4-xcex2-dimethylaminoethoxyphenyl)-1,2-diphenyl-but-1-ene, is an antiestrogen that has a palliative effect on breast cancer, but is reported to have estrogenic activity in the uterus. Gill-Sharma et al., J. Repr. Fert., 99:395 (1993), discloses that tamoxifen at 200 and 400 mg/kg/day reduces the weights of the testes and secondary sex organs in male rats.
Recently it has been reported (Osteoporosis Conf. Scrip No. 1812/13, p. 29 (Apr. 16-20, 1993)) that raloxifene, or 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl] benzo[b] thiophene, mimics the favorable action of estrogen on bone and lipids but, unlike estrogen, has minimal uterine stimulatory effect. (Jordan et al., Breast Cancer Res. Treat., 10(1):31-36 (1987)).
Neubauer et al., The Prostate, 23:245 (1993), teaches that raloxifene treatment of male rats produced regression of the ventral prostate.
Raloxifene and related compounds are described as antiestrogenic and antiandrogenic materials that are effective in the treatment of certain mammary and prostate cancers. See U.S. Pat. No. 4,418,068 and Jones et al., J. Med. Chem., 27:1057-66 (1984).
Jones et al. in U.S. Pat. No. 4,133,814 describe derivatives of 2-phenyl-3-aroylbenzothiophene and 2-phenyl-3-aroylbenzothiophene-1-oxides that are useful as antifertility agents, and also suppress the growth of mammary tumors.
Lednicer et al., J. Med. Chem., 12:881 (1969), describes estrogen antagonists of the structure 
wherein R2 is phenyl or cyclopentyl and R3 is H, xe2x80x94CH2CHOHCH2OH, or 
Bencze et al., J. Med. Chem., 10:138 (1967), prepared a series of tetrahydronaphthalenes intended to achieve separation of estrogenic, antifertility, and hypocholesterolemic activities, although they were only partially successful in doing so. These structures have the general formula: 
wherein R1 is H or OCH3, R2 is H, OH, OCH3, OPO(OC2H5)2, OCH2CH2N(C2H5)2, OCH2COOH, or OCH(CH3)COOH, and R3 is H or Cl.
U.S. Pat. No. 3,234,090 discloses compounds having estrogenic and antifungal properties, as well as procedures for the preparation of these compounds. The described compounds have the formula: 
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic carbocyclic aryl group substituted by tertiary amino-lower alkyl-oxy, in which the tertiary amino is separated from the oxy by at least two carbon atoms, R is hydrogen, an aliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical, or a heterocyclic aryl aliphatic radical, the group of the formula xe2x80x94(CnH2n-2)xe2x80x94 stands for an unbranched alkylene radical having from three to five carbon atoms and carrying the groups Ar and R, salts, N-oxides, salts of N-oxides, or quaternary ammonium compounds thereof.
U.S. Pat. No. 3,277,106 refers to basic ethers with estrogenic, hypocholesterolemic, and antifertility effects, those ethers having the formula: 
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic aryl radical substituted by at least one amino-lower alkyl-oxy group in which the nitrogen atom is separated from the oxygen atom by at least two carbon atoms, R is an aryl radical, and the portion xe2x80x94(CnH2n-2)xe2x80x94 stands for lower alkylene forming with Ph a six- or seven-membered ring, two of the ring carbon atoms thereof carry the groups Ar and R, salts, N-oxides, salts of N-oxides, and quaternary ammonium compounds thereof.
Lednicer et al., in J. Med. Chem., 10:78 (1967), and in U.S. Pat. No. 3,274,213, refer to compounds of the formula 
wherein R1 and R2 are selected from the class consisting of lower alkyl and lower alkyl linked together to form a 5 to 7 ring member saturated heterocyclic radical.
PCT publication No. WO 96/09040 A1 discloses a benzofuran compound useful for treatment of medical indications associated with post-menopausal syndrome, e.g., uterine fibroid disease, endometriosis, and aortal smooth muscle cell proliferation.
European Patent Application EP 0,826,670 A1 discloses naphthalene compounds and methods for inhibiting estrogen deficient pathologies such as lack of birth control, postmenopausal syndrome including osteoporosis, cardiovascular disease, restenosis and hyperlipidemia, prostate cancer, acne, hirsutism, dysfunctional uterine bleeding, dysmenorrhea, and atrophic vaginitis.
European Patent Application EP 0,659,424 A1 discloses benzothiophene compounds useful for treating male infertility.
U.S. Pat. No. 5,462,950 discloses the use of benzothiophene compounds for treating physical menstrual symptoms.
PCT Publication WO 96/40134 discloses methods of antagonizing or blocking calcium channels in vascular tissue comprising administering a benzothiophene compound.
U.S. Pat. No. 5,521,214 discloses methods of inhibiting environmental estrogens comprising administering a benzothiophene compound.
U.S. Pat. No. 5,554,628 discloses methods for minimizing the uterotrophic effect of tamoxifen and its analogs by administering a naphthalene compound.
PCT Publication WO 97/13764 discloses benzothiophene compounds useful for inhibiting cardiovascular disease including restenosis and atherosclerosis.
PCT Publication WO 97/13511 discloses benzothiophene compounds useful for inhibiting plasminogen activator inhibitor 1 related conditions such as major tissue damage and trauma, or multiple organ dysfunction syndrome.
European Patent Application 0,729,754 A2 discloses benzothiophene compounds useful for inhibiting estrogen positive tumors of the brain or CNS.
U.S. Pat. No. 5,670,523 discloses benzothiophene compounds useful for inhibiting musculoaponeurotic fibromatoses previously classified as desmoid tumors.
U.S. Pat. No. 5,496,828 discloses methods for inhibiting ulcerative mucositis by administering a benzothiophene compound.
PCT Publication WO 97/26876 discloses methods for increasing sphincter competence by administering a benzothiophene compound.
European Patent Application 0,826,679 A2 discloses a pharmaceutical composition useful for alleviating symptoms of postmenopausal syndromes, the composition comprising a naphthalene compound and an additional therapeutic agent such as estrogen or progestin, a benzothiophene compound such as raloxifene, a naphthyl compound having antiestrogen activity, a bisphosphonate compound such as alendronate or tiludronate, parathyroid hormone (PTH), including truncated and/or recombinant forms of PTH such as PTH (1-34), calcitonin, bone morphogenic proteins (BMPs), or combination thereof.
European Patent Application 0,702,962 A2 discloses a pharmaceutical agent for treating breast cancer, the agent comprising tamoxifen and a naphthyl compound useful for inhibiting hormone-dependent breast cancer.
U.S. Pat. No. 5,599,822 discloses a pharmaceutical composition for minimizing the bone loss effect of danazol, the composition comprising danazol and a benzothiophene compound having antiestrogen activity.
This invention relates to novel tetrahydroisoquinoline compounds that are useful as estrogen agonists and antagonists, and the pharmaceutical uses thereof.
In a first aspect, this invention provides compounds of the formula: 
wherein:
A1 is hydrogen, hydroxy, (C1-C4)alkoxy, or (C1-C4)alkanoyloxy, said (C1-C4)alkoxy or said (C1-C4)alkanoyloxy being optionally substituted by hydroxy, halo, or a partially saturated, fully saturated, or fully unsaturated five to twelve membered ring optionally having up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen, or A1 is R3xe2x80x94(C1-C4)alkoxy wherein R3is pyrrolidino, piperidino, morpholino, or dimethylamino;
A2, A3, and A4 are independently selected from hydrogen, hydroxy, (C1-C4)alkoxy, and halo;
R1 is phenyl; pyridyl; piperidinyl; (C1-C7)alkyl; adamantyl; a partially saturated, fully saturated, or fully unsaturated three to twelve membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur, and nitrogen; a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, wherein said bicyclic ring includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, wherein said bicyclic ring system includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein each of the above R1 groups is optionally substituted with up to seven fluoro atoms, or with up to three substituents independently selected from Group A, wherein Group A consists of hydroxy, halo, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, R3xe2x80x94(C1-C4)alkoxy, (C2-C4)alkenyl-COOR7 wherein R7 is hydrogen or (C1-C4)alkyl, (C0-C4)alkyl-COOR7, (C1-C4)alkanoyloxy-(C2-C4)alkenyl, (C2-C4)alkenyl-CONR4R5 wherein R4 and R5 are independently hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkylene, or (C3-C8)cycloalkyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino, (C0-C4)alkyl-CONR4R5, (C0-C4)alkyl-NR4R5, OCH2CH2NR8R9 wherein R8 and R9 are independently methyl or ethyl, or R8 and R9 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino, propyl-R8R9, and SO2xe2x80x94R6 wherein R6 is imidazolyl, thienyl, benzathienyl, or isoxazyl, optionally substituted with up to three substituents independently selected from (C1-C4)alkyl;
X is a covalent bond, (CH2)n where n is 1, 2, or 3, (C0-C1)alkylene-phenylene-(C0-C1)alkylene, CO2, (C0-C3)alkylene-COxe2x80x94(C0-C3)alkylene, or (C0-C4)alkylene-SO2xe2x80x94(C0-C4)alkylene;
R2 is (C1-C9)alkyl; (C2-C4)alkenyl; benzhydryl; a partially saturated, fully saturated, or fully unsaturated three to eight membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur, and nitrogen; a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, wherein said bicyclic ring includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, wherein said bicyclic ring system includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein said (C1-C9)alkyl is optionally substituted with one to seven fluoro substituents, or up to three substituents independently selected from Group B, wherein Group B consists of chloro, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl; wherein said (C2-C4)alkenyl is optionally substituted with up to three substituents independently selected from Group C, wherein Group C consists of halo, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl; and wherein said benzhydryl, said 5 to 8 membered ring, said bicyclic ring, and said bicyclic ring system is optionally substituted with up to three substituents independently selected from Group D, wherein Group D consists of halo, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, imidazolyl, amino, (C1-C4)alkylcarbonylamino, and (C1-C4)alkylcarbonyl; and
p is 0, 1, or 2;
with the proviso that
when X is (CH2)2 or (CH2)3, p is 0, and R1 is phenyl or phenyl substituted with a single chloro, fluoro, bromo, hydroxy, methoxy, pyrrolidinoethoxy, piperidinoethoxy, or morpholinoethoxy substituent, then R2 is not phenyl, methoxyphenyl, tert-butyl, or cyclopentyl;
when X is CH2, (CH2)2, COCH2, or CH2CO, A1 is hydrogen, and R1 is phenyl, then R2 is not phenyl; and
when X is a covalent bond, p is 0, A1 is hydrogen or methoxy, and R1 is phenyl or phenyl substituted with a single chloro, fluoro, bromo, methoxy, pyrrolidinoethoxy, or piperidinoethoxy substituent, then R2 is not phenyl or m-fluorophenyl.
In a preferred embodiment of the first aspect, A1 is hydroxy; A2, A3, and A4 are hydrogen; and p is 0.
In another preferred embodiment of the first aspect, R1 is phenyl, pyridyl, (C1-C4)alkyl, adamantyl, naphthyl, or a partially saturated, fully saturated, or fully unsaturated five to six membered ring optionally having up to two heteroatoms selected independently from oxygen, sulfur, and nitrogen; wherein each of said R1 groups is optionally substituted with up to seven fluoro atoms, or with up to three substituents independently selected from Group A.
In another preferred embodiment of the first aspect, R1 is phenyl, cyclohexyl, pyridyl, thienyl, isopropyl, or adamantyl; wherein each of said R1 groups is optionally substituted with up to seven fluoro atoms, or with up to three substituents independently selected from Group A.
In another preferred embodiment of the first aspect, R1 is phenyl or cyclohexyl; wherein each of said R1 groups is optionally substituted with up to seven fluoro atoms, or with up to three substituents independently selected from Group A.
In another preferred embodiment of the first aspect, each of said R1 groups is substituted with up to three halo atoms, or with one substituent selected from hydroxy, (C1-C2)alkoxy, pyrrolidino-(C1-C4)alkoxy, dimethylamino, (C2-C4)alkenyl-COOR7, COOR7, (C2-C4)alkenyl-CONR4R5 wherein R4 and R5 are independently hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, xe2x80x94(CH2CH2xe2x80x94Oxe2x80x94CH3), or (C5-C6)cycloalkyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form piperidino or morpholino, or SO2xe2x80x94R6 wherein R6 is imidazolyl optionally substituted with up to three substituents independently selected from (C1-C4)alkyl.
In another preferred embodiment of the first aspect, each of said R1 groups is substituted with up to three fluoro atoms, or with one substituent selected from iodo, chloro, bromo, hydroxy, methoxy, pyrrolidino-ethoxy, dimethylamino, COOR7 wherein R7 is hydrogen or methyl, or ethenyl-CONR4R5 wherein R4 and R5 are both methyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form piperidino or morpholino.
In another preferred embodiment of the first aspect, each of said R1 groups is substituted with one hydroxy or pyrrolidino-ethoxy.
In another preferred embodiment of the first aspect, X is a covalent bond, CH2, CH2-phenylene, CO2, COxe2x80x94(C0-C2)alkylene, or SO2xe2x80x94(C0-C2)alkylene.
In another preferred embodiment of the first aspect, X is a covalent bond, CO, or SO2.
In another preferred embodiment of the first aspect, R2 is (C1-C7)alkyl; propenyl; a partially saturated, fully saturated, or fully unsaturated five to seven membered ring optionally having up to two heteroatoms selected independently from oxygen, sulfur, and nitrogen; a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, wherein said bicyclic ring includes up to two oxygen atoms; or biphenyl; wherein said (C1-C7)alkyl is optionally substituted with one to seven fluoro substituents, or up to three substituents independently selected from Group B; wherein said propenyl is optionally substituted with up to three substituents independently selected from Group C; and wherein each of said 5-7 membered ring, said bicyclic ring, and said biphenyl is optionally substituted with up to three substituents independently selected from Group D. In an even more preferred embodiment, each of said (C1-C7)alkyl and said propenyl is substituted with one to three fluoro substituents, or up to two substituents independently selected from amino and methylcarbonyl; and wherein each of said 5-7 membered ring, said bicyclic ring, and said biphenyl is substituted with up to three fluoro substituents, or up to two substituents independently selected from hydroxy, (C1-C3)alkyl, amino, and methylcarbonyl.
In another preferred embodiment of the first aspect, R2 is methyl, t-butyl, phenyl, cyclohexyl, isoxazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl; wherein each of said methyl or t-butyl is optionally substituted with one to seven fluoro substituents, or up to three substituents independently selected from Group B; and wherein each of said phenyl, cyclohexyl, isoxazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl is optionally substituted with up to three substituents independently selected from Group D.
In another preferred embodiment of the first aspect, R2 is trifluoromethyl or phenyl; wherein said phenyl is optionally substituted with up to three substituents independently selected from Group D.
In another preferred embodiment of the first aspect,
A1 is hydroxy;
A2, A3, and A4 are hydrogen;
p is 0;
R1 is phenyl, cyclohexyl, pyridyl, thienyl, isopropyl, or adamantyl; wherein each of said R1 groups is optionally substituted with up to three fluoro atoms, or with one substituent selected from iodo, chloro, bromo, hydroxy, methoxy, pyrrolidino-ethoxy, dimethylamino, COOR7 wherein R7 is hydrogen or methyl, or ethenyl-CONR4R5 wherein R4 and R5 are both methyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form piperidino or morpholino;
X is a covalent bond, CH2, CH2-phenylene, CO2, COxe2x80x94(C0-C2)alkylene, or SO2xe2x80x94(C0-C2)alkylene; and
R2 is methyl, t-butyl, phenyl, cyclohexyl, isoxazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl; wherein each of said methyl or t-butyl is optionally substituted with one to three fluoro substituents, or up to two substituents independently selected from amino and methylcarbonyl; and wherein each of said phenyl, cyclohexyl, isoxazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl is optionally substituted with up to three fluoro substituents, or up to two substituents independently selected from hydroxy, (C1-C3)alkyl, amino, and methylcarbonyl.
Some of the more preferred compounds of the first aspect of the present invention include 1-(4-hydroxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol; 3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenyl]-1-piperidin-1-yl-propenone; 3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenyl]-1-morpholin-4-yl-propenone; 3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenyl]-N,N-dimethyl-acrylamide; 2-benzyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol; 2,2,2-trifluoro-1-[6-hydroxy-1-(4-hydroxyphenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone; 2-benzenesulfonyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol; and 2-(4-isopropylbenzenesulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol.
In another preferred embodiment of the first aspect,
said compound is of formula (I);
A1 is hydroxy, (C1-C4)alkoxy, (C1-C4)alkanoyloxy, or pyrrolidino-ethoxy;
A2, A3, and A4 are hydrogen;
p is 0 or 1;
R1 is (C1-C4)alkyl, (C4-C7)cycloalkyl, adamantyl, phenyl, pyridyl, or thienyl, wherein each of said phenyl, pyridyl, or thienyl groups is optionally substituted with up to three fluoro atoms, or with one substituent selected from iodo, chloro, bromo, hydroxy, methoxy, dimethylamino, OCH2CH2NR8R9, COOR7, ethenyl-COOR7, or ethenyl-CONR4R5 wherein R4 and R5 are both methyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, hexamethyleneimino, or morpholino;
X is a covalent bond, CH2, CH2-phenylene, CO2, COxe2x80x94(C0-C2)alkylene, or SO2xe2x80x94(C0-C2)alkylene; and
R2 is (C1-C7)alkyl, phenyl, benzyl, thienyl, (C5-C7)cycloalkyl, isoxazolyl, imidazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl, wherein said (C1-C7)alkyl is optionally substituted with one to three fluoro substituents, or up to two substituents independently selected from amino and methylcarbonyl, and wherein each of said phenyl, thienyl, (C5-C7)cycloalkyl, isoxazolyl, tetrahydropyranyl, naphthyl, and benzodioxolyl is optionally substituted with up to three fluoro substituents, or up to two substituents independently selected from hydroxy, methoxy, (C1-C3)alkyl, amino, and methylcarbonyl.
In another preferred embodiment of the first aspect, said compound is of formula (II).
In another preferred embodiment of the first aspect,
said compound is of formula (II);
A1 is hydroxy, (C1-C4)alkoxy, or (C1-C4)alkanoyloxy;
A2, A3, and A4 are hydrogen;
p is 0 or 1;
R1 is (C1-C4)alkyl, (C4-C7)cycloalkyl, adamantyl, phenyl, pyridyl, or thienyl, wherein each of said phenyl, pyridyl, thienyl, or (C5-C7)cycloalkyl groups is optionally substituted with up to three fluoro atoms, or with one substituent selected from iodo, chloro, bromo, hydroxy, methoxy, dimethylamino, OCH2CH2NR8R9, COOR7, or ethenyl-CONR4R5 wherein R4 and R5 are both methyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, hexamethyleneimino, or morpholino;
X is a covalent bond, CH2, CH2-phenylene, CO2, COxe2x80x94(C0-C2)alkylene, or SO2xe2x80x94(C0-C2)alkylene; and
R2 is (C1-C7)alkyl, phenyl, benzyl, thienyl, (C5-C7)cycloalkyl, isoxazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl, wherein said (C1-C7)alkyl is optionally substituted with one to three fluoro atoms, or up to two substituents independently selected from amino and methylcarbonyl, and wherein each of said phenyl, thienyl, cyclohexyl, isoxazolyl, tetrahydropyranyl, naphthyl, and benzodioxolyl is optionally substituted with up to three fluoro atoms, or up to two substituents independently selected from hydroxy, methoxy, and (C1-C3)alkyl.
One of the more preferred compounds of the first aspect of the present invention, wherein the compound is of formula (II) is 2,2,2-trifluoro-1-[7-hydroxy-4-(4-hydroxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone.
In a second aspect, this invention provides compounds of the formula: 
wherein:
A1 is hydrogen, hydroxy, (C1-C4)alkoxy, or (C1-C4)alkanoyloxy, said (C1-C4)alkoxy or said (C1-C4)alkanoyloxy being optionally substituted by hydroxy, halo, or a partially saturated, fully saturated, or fully unsaturated five to twelve membered ring optionally having up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen, or A1 is R3xe2x80x94(C1-C4)alkoxy wherein R3 is pyrrolidino, piperidino, morpholino, or dimethylamino;
A2, A3, and A4 are independently selected from hydrogen, hydroxy, (C1-C4)alkoxy, and halo;
R1 is phenyl; pyridyl; piperidinyl; (C1-C7)alkyl; adamantyl; a partially saturated, fully saturated, or fully unsaturated three to twelve membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur, and nitrogen; a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, wherein said bicyclic ring includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, wherein said bicyclic ring system includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein each of the above R1 groups is optionally substituted with up to seven fluoro atoms, or with up to three substituents independently selected from Group A, wherein Group A consists of hydroxy, halo, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, R3xe2x80x94(C1-C4)alkoxy, (C2-C4)alkenyl-COOR7 wherein R7 is hydrogen or (C1-C4)alkyl, (C0-C4)alkyl-COOR7, (C1-C4)alkanoyloxy-(C2-C4)alkenyl, (C2-C4)alkenyl-CONR4R5 wherein R4 and R5 are independently hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkylene, or (C3-C8)cycloalkyl, or R4 and R5 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino, (C0-C4)alkyl-CONR4R5, (C0-C4)alkyl-NR4R5, OCH2CH2NR8R9 wherein R8 and R9 are independently methyl or ethyl, or R8 and R9 taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, or hexamethyleneimino, propyl-R8R9, and SO2xe2x80x94R6 wherein R6 is imidazolyl, thienyl, benzathienyl, or isoxazyl, optionally substituted with up to three substituents independently selected from (C1-C4)alkyl;
X is (C0-C1)alkylene-phenylene-(C0-C1)alkylene, CO2, CO, (C1-C3)alkylene-COxe2x80x94(C1-C3)alkylene, (C0-C3)alkylene-COxe2x80x94(C2-C3) alkylene, (C2-C3)alkylene-COxe2x80x94(C0-C3)alkylene, or (C0-C4)alkylene-SO2xe2x80x94(C0-C4)alkylene;
R2 is (C1-C9)alkyl; (C2-C4)alkenyl; benzhydryl; a partially saturated, fully saturated, or fully unsaturated three to eight membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur, and nitrogen; a bicyclic ring consisting of two fused independently partially saturated, fully saturated, or fully unsaturated five to six membered rings, wherein said bicyclic ring includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; or a bicyclic ring system consisting of two rings joined by a covalent bond, said rings being independently partially saturated, fully saturated, or fully unsaturated three to eight membered rings, wherein said bicyclic ring system includes up to four heteroatoms independently selected from oxygen, sulfur, and nitrogen; wherein said (C1-C9)alkyl is optionally substituted with one to seven fluoro substituents, or up to three substituents independently selected from Group B, wherein Group B consists of chloro, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl; wherein said (C2-C4)alkenyl is optionally substituted with up to three substituents independently selected from Group C, wherein Group C consists of halo, (C1-C4)alkoxy, amino, and (C1-C4)alkylcarbonyl; and wherein said benzhydryl, said 5 to 8 membered ring, said bicyclic ring, and said bicyclic ring system is optionally substituted with up to three substituents independently selected from Group D, wherein Group D consists of halo, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, imidazolyl, amino, (C1-C4)alkylcarbonylamino, and (C1-C4)alkylcarbonyl; and
p is 0, 1, or 2.
In a third aspect, this invention provides methods for treating or preventing a disease, disorder, condition, or symptom mediated by an estrogen receptor and/or caused by lowered estrogen level in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound of the present invention.
In preferred embodiments of the third aspect, a therapeutically effective amount of a compound of the present invention is combined with a therapeutically effective amount of an anabolic agent, a prodrug thereof, or a pharmaceutically acceptable salt of said anabolic agent or said prodrug; a growth hormone or a growth hormone secretagogue, a prodrug thereof, or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug; a prostaglandin agonist/antagonist, a prodrug thereof, or a pharmaceutically acceptable salt of said prostaglandin agonist/antagonist or said prodrug; or a parathyroid hormone or sodium fluoride.
In another preferred embodiment of the third aspect, said disease, disorder, condition, or symptom is perimenopausal or postmenopausal syndrome, osteoporosis, atrophy of skin or vagina, elevated serum cholesterol levels, cardiovascular disease, Alzheimer""s disease, a reduction or prevention of reduction in cognitive function, an estrogen dependent cancer, breast or uterus cancer, a prostatic disease, benign prostatic hyperplasia, or prostate cancer.
In another preferred embodiment of the third aspect, said disease, disorder, condition, or symptom is obesity, endometriosis, bone loss, uterine fibrosis, aortal smooth muscle cell proliferation, lack of birth control, acne, hirsutism, dysfunctional uterine bleeding, dysmenorrehea, male infertility, impotence, psychological and behavioral symptoms during menstruation, ulcerative mucositis, uterine fibroid disease, restenosis, atherosclerosis, musculoaponeurotic fibromatosis, alopecia, wound-healing, scarring, auto immune disease, cartilage degeneration, delayed puberty, demyelinating disease, dysmyelinating disease, hypoglycemia, lupus erythematosus, myocardial infarction, ischemia, thromboembolic disorder, obessive compulsive disorder, ovarian dysgenesis, post menopausal CNS disorder, pulmonary hypertension, reperfusion damage, resistant neoplasm, rheumatoid arthritis, seborrhea, sexual precocity, thyroiditis, Turner""s syndrome, or hyperlipidemia.
In another preferred embodiment of the third aspect, said method is useful for blocking a calcium channel, inhibiting an environmental estrogen, minimizing the uterotropic effect of tamoxifen or an analog thereof, removing fibrin by inhibiting plasminogen activators, inhibiting estrogen positive primary tumors of the brain and CNS, increasing sphincter competence, increasing libido, inhibiting fertility, oxidizing low density lipoprotein, increasing macrophage function, expressing thrombomodulin, or increasing levels of endogenous growth hormone.
In a fourth aspect, this invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable vehicle, carrier, or diluent.
In a fifth aspect, this invention provides kits useful for treating or preventing a disease, disorder, condition, or symptom mediated by an estrogen receptor and/or caused by lowered estrogen levels, said kit comprising a compound of the present invention and a pharmaceutically acceptable vehicle, carrier, or diluent in a dosage form, and a container for containing said dosage form.
In a preferred embodiment of the fifth aspect, said kit also comprises an anabolic agent, a prodrug thereof, or a pharmaceutically acceptable salt of said anabolic agent or said prodrug; a growth hormone or a growth hormone secretagogue, a prodrug thereof, or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug; a prostaglandin agonist/antagonist, a prodrug thereof, or a pharmaceutically acceptable salt of said prostaglandin agonist/antagonist or said prodrug; or a parathyroid hormone or sodium fluoride.
Halo or halogen refers to chloro, bromo, iodo and fluoro.
Estrogen agonists are herein defined as chemical compounds capable of binding to estrogen receptor sites in mammalian tissue and mimicking the action(s) of estrogen in one or more tissues.
Estrogen antagonists are herein defined as chemical compounds capable of binding to estrogen receptor sites in mammalian tissue and blocking the action(s) of estrogen or estrogen agonists in one or more tissues.
As used in this application, prostatic disease means benign prostatic hyperplasia or prostatic carcinoma.
A xe2x80x9ccompoundxe2x80x9d, when used to refer to compounds of the present invention, includes within its scope not just the specific compound(s) listed or described, but also alternative forms of the compound, such as prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable salts of the prodrug, solvates, hydrates, and the like.
A prodrug is a chemical compound that, in its present form, has little or reduced pharmaceutical activity, but which, upon introduction into its biological environment, is readily converted into an active drug form. An exemplary prodrug is an ester of a drug, where upon introduction into a patient, the ester is cleaved to produce the active drug.
A xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound is an amount that is sufficient to cure, prevent, or alleviate a disease, disorder, condition, or symptom.
An xe2x80x9canabolic agentxe2x80x9d is any compound that is capable of promoting synthetic metabolic reactions in a patient. In a preferred embodiment, anabolic agents are useful in promoting wound healing.
A xe2x80x9cgrowth hormone or growth hormone secretagoguexe2x80x9d is a naturally occurring growth hormone as understood by those skilled in the art, a compound that mimics one or more actions of a naturally occurring growth hormone, or a compound that stimulates the release of naturally occurring growth hormone in a patient.
A xe2x80x9cprostaglandin agonist or antagonistxe2x80x9d is any compound that is capable of agonizing or antagonizing the activity of a prostaglandin in a patient.
Those of skill in the art will recognize that certain substituents listed in this invention will be chemically incompatible with one another or with the heteroatoms in the compounds, and will avoid these incompatibilities in selecting compounds of this invention. Likewise, certain functional groups may require protecting groups during synthetic procedures as will be recognized by those of skill in the art.
Those of skill in the art will also recognize that certain compounds of this invention will consist of multiple possible geometric configurations, or isomers. All such isomers are included in this invention.
The pharmaceutical compositions and methods of this invention comprise, as an active ingredient, a compound of formula I or II. The pharmaceutically acceptable salts of the compounds of formula I and II are salts of non-toxic type commonly used, such as salts with organic acids (e.g., formic, acetic, trifluoroacetic, citric, maleic, tartaric, methanesulfonic, benzenesulfonic, toluenesulfonic acids, and the like), inorganic acids (e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids, and the like), amino acids (e.g., aspartic acid, glutamic acid, and the like), alkali metals (e.g., sodium, potassium, and the like), and alkaline earth metals (e.g., calcium, magnesium, and the like). These salts may be prepared by methods known to those of skill in the art.
The compounds of this invention may be administered to animals (including humans) orally, parenterally, topically, or otherwise, in any conventional form of preparation, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, and the like.
The pharmaceutical compositions of this invention can be prepared by methods commonly employed using conventional additives, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, and the like), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylprrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, and the like), disintegrators (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, calcium citrate, and the like), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, sodium lauryl sulfate, and the like), flavoring agents (e.g., citric acid, menthol, glycine, orange powder, and the like), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, propylparaben, and the like), stabilizers (e.g., citric acid, sodium citrate, acetic acid, and the like), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, aluminum stearate, and the like), dispersing agents (e.g., hydroxypropylmethylcellulose and the like), diluents (e.g., water, alcohol, glycerin, and the like), and base waxes (e.g., cocoa butter, white petrolatum, polyethylene glycol, and the like).
The compounds of this invention may be administered once a day or in multiple daily doses, with a preferred daily dosage of about 0.001 to about 100 mg in adult human patients. This dosage may be properly varied depending on the age, body weight, and medical condition of the patient, as well as the mode of administration. A more preferred daily dose is about 1.0 to about 10 mg in human patients. One dose per day is preferred. Controlled release, sustained release, and/or delayed release oral or parenteral compositions may be used.
General Reaction Schemes
Compounds of this invention are readily prepared by the reactions illustrated in the schemes below.
If required in the following processes, active groups may be protected with a suitable protecting group such as benzyl, p-toluenesulfonyl, methyl, p-methoxybenzyl, and the like, and the protecting group may subsequently be removed at a later stage in the synthesis. The protection and removal of the protecting groups may be carried out according to procedures known to those skilled in the art (e.g., procedures disclosed in Protective Groups in Organic Synthesis by T. W. Greene, published by John Wiley and Sons (1991)).
General Reaction Scheme A
A compound of formula (Ia) (i.e., a compound of formula (I) wherein X is COxe2x80x94(CH2)y, and y is 0-3) may be prepared according to the procedures illustrated in Scheme A. 
As illustrated in Scheme A, a phenethyl amine of formula (II) is coupled with a carboxylic acid of formula (III) to give the benzamide of formula (V). Compound (V) is subjected to cyclodehydration to give the dihydroisoquinoline of formula (VI). Dihydroisoquinoline (VI) is reduced to the tetrahydroisoquinoline of formula (VII). Then, compound (VII) may be reacted with a desired acid anhydride, acid chloride, or other coupling agent to give compound (Ia). Alternatively, compound (VII) may be reacted with a desired acid in the presence of 1-propanephosphonic acid cyclic anhydride, Et3N, and DMAP in dichloromethane (CH2Cl2) to yield compound (Ia).
The coupling of compounds (II) and (III) is carried out in the presence of a coupling agent for peptide synthesis, preferably with an additive. Suitable coupling agents include water-soluble diimides such as N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)-carbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and suitable additives include 1-hydroxybenzotriazole (HOBt) and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine. This reaction mixture is preferably stirred at a temperature between about 0xc2x0 C. to room temperature (i.e., about 25xc2x0 C.), for about 12 to 60 hours in a reaction inert solvent such as CH2Cl2, preferably under nitrogen.
Cyclodehydration of the intermediate compound (V) is carried out in a reaction inert solvent such as 1,2-dichloroethane in the presence of phosphorus pentachloride under nitrogen, or neat using phosphorus oxychloride under nitrogen. Phosphorus pentachloride is added to the solution of compound (V) at about 0xc2x0 C., then the reaction mixture is refluxed for about 1 to 24 hours. The reaction of compound (V) and phosphorus oxychloride is carried out at about the reflux temperature of the reaction mixture for about 1 to 48 hours.
The reduction of compound (VI) to compound (VII) is typically carried out in the presence of sodium borohydride in a reaction inert solvent such as methanol or tetrahydrofuran, at from about 0xc2x0 C. to about room temperature, for about 1 to 12 hours, preferably under nitrogen. The reaction is quenched with water.
The intermediate compound (VII) thus obtained is reacted with a desired acid anhydride or acid chloride to yield compound (Ia) according to amide formation procedures known to those skilled in the art. This reaction is performed in the presence of a base such as triethylamine (Et3N), in a reaction inert solvent such as CH2Cl2, for about 1 to 72 hours, at about 0xc2x0 C. to about room temperature. This reaction is preferably performed under nitrogen.
Alternatively, compound (V) may be prepared by reacting compound (II) with an acyl chloride of formula (IV) in the presence of a base such as triethylamine in a reaction inert solvent. Suitable solvents include dichloromethane, tetrahydrofuran (THF), CHCl3, 1,2-dichloroethane, dioxane, toluene, benzene, and the like, with THF being the most preferred. This reaction is preferably carried out at a temperature of about 0xc2x0 C. to 30xc2x0 C., most preferably about 25xc2x0 C., under nitrogen, for about 1 to 24 hours, preferably about 12 hours. If required, a catalyst such as 4-(dimethylamino)pyridine, scandium triflate, tributyl phosphine, or the like may be added to the reaction mixture.
Intermediate compound (VI) may be substituted with a desired substituent on R1 and subsequently subjected to the remaining processes illustrated in Scheme A. This substitution reaction is performed according to procedures known to those skilled in the art. For example, compound (VI) wherein R1 is piperidin-4-yl may be reacted with a heteroaryl sulfonyl chloride in the presence of a base such as triethylamine in a reaction inert solvent such as dichloroethane to yield a sulfonamide. This reaction is preferably carried out at about room temperature, under nitrogen, for about 1 to 24 hours, preferably about 2 to 20 hours.
A compound of formula (I) of this invention wherein X is xe2x80x94(CH2)zxe2x80x94SO2xe2x80x94 may be prepared by reacting compound (VII) with a sulfonyl chloride of formula R2xe2x80x94(CH2)zxe2x80x94SO2xe2x80x94Cl according to known procedures. For example, this reaction may be carried out in the presence of triethylamine in a reaction inert solvent such as tetrahydrofuran (THF) at about room temperature for about 1 to 24 hours under nitrogen.
A compound of formula (I) of this invention wherein X is a covalent bond, (CH2)n, or (CH2)x-phenyl (wherein x is 0 or 1), may also be prepared by reacting compound (VII) with an aldehyde of formula R2xe2x80x94Xxe2x80x94CHO according to known procedures. This reaction is typically performed in the presence of a reducing agent such as sodium cyanoborohydride in a suitable solvent such as methanol.
A compound of formula (I) of this invention wherein X is CO2 may be prepared by reacting compound (VII) with either a dicarbonate of formula (R2OCO)2O or a chloroformate of formula R2OCOCl in the presence of a base such as triethylamine in a suitable solvent such as THF at about room temperature for about 1 to 24 hours, preferably under nitrogen.
General Reaction Scheme B
A compound of formula (Ib) (i.e., a compound of formula (I) wherein X is a covalent bond and R2 is an optionally substituted ring moiety) may be prepared according to the procedures illustrated in Scheme B. 
A benzyl acid of formula (VIII) is reacted with an amine of formula (IX) to give an amide, which is then reduced (this step not shown) to give the phenethyl amine of formula (X) according to known procedures (see, for example, Nagarajan et al., Ind. J. Chem., 24B:83-97 (1985)). Compound (X) thus obtained is reacted with a carboxylic acid of formula (XI) to give the benzamide of formula (XII). The compound of formula (XII) is subjected to cyclodehydration followed by reduction, preferably with NaBH4 in methanol, to give the tetrahydroisoquinoline (Ib).
The reaction of compound (X) with compound (XI) is carried out in the presence a base such as triethylamine, in a reaction inert solvent such as dichloromethane, THF, CHCl3, or dioxane, preferably in the presence of a coupling agent such as 1-propanephosphonic acid cyclic anhydride (PPAA), EDC, or a mixture thereof, and a catalytic amount of an additive such as HOBt or 4-dimethylaminopyridine (DMAP), at about 0xc2x0 C. to room temperature for about 1 to 36 hours.
The cyclodehydration of compound (XII) may be carried out according to procedures analogous to those described for in Scheme A.
Alternatively, compound (X) may be reacted with an acyl chloride of formula (IV) to give an amide (XII). This reaction may be performed according to procedures analogous to those described in Scheme A.
Compound (XI) may be substituted at its R1 moiety with a desired substituent. For example, when R1 is aryl aldehyde, compound (XI) is coupled with a carboalkoxytriphenylphosphorane in the presence of a base such as sodium hydroxide in a reaction inert solvent such as tetrahydrofuran (THF). This reaction is performed at about room temperature for about 1 to 12 hours.
General Reaction Scheme C
Scheme C illustrates methods to produce a compound of formula (Ic), namely a compound of formula (I) wherein A1 is hydroxy and X is a covalent bond, (CH2)n, or (CH2)x-phenyl (wherein x is 0 or 1), starting from a compound of formula (Ia). In this scheme, xe2x80x9cProxe2x80x9d is a hydroxy protecting group. 
For example, compound (Ia) wherein A1 is hydroxy, X is CO, and R2 is CF3 is first protected with a suitable hydroxy protecting group to obtain the compound of formula (XIII), which is converted to the compound of formula (XIV), which is coupled with a suitable acyl chloride of formula R2COCl to obtain the compound of formula (XV), which is finally deprotected to yield the desired compound (Ic).
While any hydroxy protecting groups known to those skilled in the art may be used to protect compound (Ia), a benzyl or methyl group is preferably used. The protection is typically carried out by reacting compound (Ia) wherein A1 is hydroxy with benzyl bromide in the presence of sodium hydride in a reaction inert solvent such as DMF at about 0xc2x0 C. to 100xc2x0 C. under nitrogen for about 1 to 12 hours, preferably about 4 hours.
Conversion of compound (XIII) is performed according to known procedures. This conversion is conveniently carried out in the presence of an inorganic base such as K2CO3, in a reaction inert solvent such as methanol or ethanol under N2 for about 1 to 24 hours, preferably about 12 to 24 hours.
The coupling reaction of compound (XIV) with a desired acyl chloride of formula R2COCl is preferably performed in the presence of triethylamine in THF at about room temperature under nitrogen for about 1 to 24 hours.
The hydroxy protecting group of compound (XV) may be removed by known procedures. For example, this reaction may be performed in the presence of a source of H2 and a catalyst such as 20% Pd(OH)2/C, in a reaction inert solvent such as methanol, under nitrogen, at about the reflux temperature of the reaction mixture for about 1 to 4 hours.
Compound (I) wherein R1 is aryl substituted by an alkenylamide group may be obtained by reacting compound (I) wherein R1 is iodophenyl with a suitable alkenylamide. This reaction may be performed in the presence of a catalyst such as Pd(PPh3)4 and a base such as triethylamine in a reaction inert solvent such as N,N-dimethylformamide (DMF) at about 60xc2x0 C. to 100xc2x0 C. for about 1 to 12 hours. The alkenylamide may be prepared by known methods, for example, by reacting a secondary amine with an acyl halide such as acryloyl chloride. This reaction is performed in the presence of a base such as triethylamine in a reaction inert solvent such as dichloroethane at about room temperature for about 1 to 12 hours.
Compound (I) wherein A1 is hydroxy may be obtained by converting compound (Ia) wherein A1 is methoxy. This conversion is performed in the presence of boron tribromide in a suitable solvent such as dichloromethane at about xe2x88x9278xc2x0 C. to room temperature under nitrogen for about 1 to 12 hours. If required, this conversion may be quenched by adding a suitable solvent such as methanol.
The hydroxy group at the 6-position of the tetrahydroisoquinoline ring of compound (I) may be converted into an optionally substituted (C1-C4 alkyl)xe2x80x94CO. For example, the hydroxy may be coupled with 1-(2-chloroethyl)pyrrolidine hydrochloride in the presence of a condensing agent such as sodium hydride in a reaction inert solvent such as DMF. This reaction is preferably performed at about room temperature to the reflux temperature of the reaction mixture, more preferably at about 100xc2x0 C., under nitrogen, for about 1 to 8 hours, preferably about 4 to 5 hours.
A substituent attached to a ring moiety of R1 of compound (I) may be converted to another substituent. For example, the hydroxy substituent on the R1 ring moiety may be converted to 2-pyrrolidin-1-yl-ethoxy according to procedures analogous to those for the coupling reaction of hydroxy at the 6-position of the tetrahydroisoquinoline ring of compound (I) with 1-(2-chloroethyl)pyrrolidine hydrochloride.
Compounds (II), (III), (IV), (VIII), (IX) and (XI) are known compounds and are readily prepared according to procedures well known to those skilled in the art.
General Reaction Scheme D
A compound of formula (XXI) (i.e., a compound of formula (II) lacking the R2 group) may be prepared according to the procedures illustrated in Scheme D. 
Compounds of formula (XXI) can be prepared under standard reaction conditions analogous to those well known in the art (e.g., Grethe et al., J. Org. Chem., 33(2):491 (1968)). For example a suitably protected dihydro-1H-isoquinolin-4-one of formula (XXII) can be treated with a nucleophile of formula (XXIII) such as substituted phenyl lithium to give the alcohol of formula (XXIV). The reaction is typically run in an inert solvent such as THF, 1,2 dimethoxyethane, or diethyl ether, and a temperature range of xe2x88x9278xc2x0 C. to room temperature is preferred.
The alcohol (XXIV) can be reduced to the tetrahydroisoquinoline of formula (XXV) under suitable conditions (e.g., hydrogenation over a metal catalyst such as palladium). Another option for the reaction is to perform the reduction with a trialkylsilane in the presence of a strong acid such as trifluoroacetic acid. The reaction is typically run in an inert solvent at a temperature range of 0xc2x0 C. to 60xc2x0 C. 
The compounds of formula (XXI) can be treated with an acid chloride of formula (XXVI) or an acid anhydride of formula (XXVII) in the presence a tertiary amine base such as triethylamine or DMAP to give an amide of formula (XXVIII). The acid chlorides of formula (XXVI) and acid anhydride of formula (XXVII) are commercially available or can be prepared from carboxylic acids by procedures known to those skilled in the art.
Another synthetic route for preparing the compounds of formula (XXVIII) involves treating a compound of formula (XXI), preferably at room temperature, with a carboxylic acid of formula (XXIX) in the presence of a coupling agent (e.g., dicyclohexylcarbodiimide (DCC), 1-(3xe2x80x2-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or 1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a solvent such as dichloromethane, chloroform, or dimethylformamide. Optionally, agents such as HOBt maybe added to the reaction. 
Compounds of formula (XXX) can be prepared by reacting the amines of formula (XXI) with a sulfonyl chloride of formula (XXXI) in the presence of a base such as triethylamine, DMAP, or NMO in a suitable solvent such as dichloromethane, chloroform, or dimethylformamide. The reactions can be run in temperature range of xe2x88x9220xc2x0 C. to 60xc2x0 C., though room temperature is preferred. 
Compounds of formula (XXXII) can be prepared by reacting the amines of formula (XXI) with a chloroformate of formula (XXXIII) in the presence of a base such as triethylamine, DMAP, NMO, or sodium hydrogen carbonate in a suitable solvent such as dichloromethane, chloroform, aqueous or anhydrous tetrahydrofuran, or dimethylformamide. The reaction can be run at 0xc2x0 C. to 60xc2x0 C., though room temperature is preferred.
General Reaction Scheme E
A compound of formula (XXI) (i.e., a compound of formula (II) lacking the R2 group) may also be prepared according to the procedures illustrated in Scheme E. 
An alternative and more preferable synthesis of compounds of formula (XXI) involves reacting an alpha halogenated ketone of formula (XXXIV) with a suitably protected ammonia equivalent, preferably benzylamine, to give an amino-ketone of formula (XXXV). It will be obvious to anyone skilled in the art that the order of some of the next steps may be reversed. The compound of formula (XXXV) can be reduced with a suitable reducing agent, preferably sodium borohydride, di-isobutyl aluminum hydride (DIBAL-H), or lithium aluminum hydride in a suitable solvent. Typically, sodium borohydride reactions are run in protic solvents such as methanol or ethanol, in the temperature range of xe2x88x9210xc2x0 C. to 40xc2x0 C. (but preferably at about 0xc2x0 C.), and the DIBAL-H or lithium aluminum hydride reactions are preferably run in dichloromethane or THF in the temperature range of xe2x88x9278xc2x0 C. to 30xc2x0 C. (preferably at about 0xc2x0 C.) to give the amino alcohol of formula (XXXVI). In the next step, the amino alcohol of formula (XXXVI) is condensed with an aldehyde of formula (XXXVII) to give initially an iminium salt of formula (XXXVIII). The iminium salt of formula (XXXVIII) is reduced in situ with a reducing agent such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride in a solvent such as dichloromethane, chloroform, 1,2 dichloroethane, methanol, or ethanol to give the amino alcohol of formula (XXXIX). For the latter reduction reaction, a temperature range of xe2x88x9210xc2x0 C. to 50xc2x0 C. can be employed but a temperature of about 0xc2x0 C. is preferred.
The amino alcohol of formula (XXXIX) can be cyclodehyrated in the presence of a strong acid such as sulfuric acid or trifluoroacetic acid in a solvent such as dichloromethane, chloroform, or 1,2 dichloroethane in a temperature range of 0xc2x0 C. to 60xc2x0 C. to give (after appropriate deprotection) the tetrahydroisoquinoline of formula (XXI).
General Reaction Scheme F
A compound of formula (XXIX) (i.e., the amino alcohol intermediary shown in Scheme E) may be prepared according to the alterntive procedures illustrated in Scheme F. 
Another option for the synthesis of amino alcohol of formula (XXXIX) is via the amide of formula (XL), which can be prepared by methods known to those of ordinary skill from the amino alcohol (XXXVI). Such methods may include taking the amino-alcohol of formula (XXXVI) and treating this with an acid chloride of formula (XLI) in the presence of a tertiary amine base such as triethylamine or DMAP. The acid chlorides of formula (XLI) are commercially available or can be prepared from carboxylic acids by procedures known to those of ordinary skill in the art. Another method of preparing the amides of formula (XL) involves treating an amino alcohol of formula (XXXVI) with a carboxylic acid of formula (XLII) in the presence of a coupling agent (e.g., DCC, EDC, or PPAA) and a suitable base (e.g., triethylamine, DMAP, or NMO) in a solvent such as dichloromethane, chloroform, or dimethylformamide. Optionally, agents such as HOBt maybe added to the reaction. Typically, the reaction is run in the temperature range of 0xc2x0 C. to 50xc2x0 C., with room temperature being preferred.
The amides of formula (XL) can then be reduced to an amino-alcohol of formula (XXXIX) by reaction with a reducing agent such as lithium aluminum hydride or borane in a suitable solvent such as tetrahydrofuran or 1,2 dimethoxyethane at xe2x88x9210xc2x0 C. to 100xc2x0 C. (with 0xc2x0 C. being preferred).
Reactive groups not involved in the above processes can be protected with standard protecting groups during the reactions and removed by standard procedures (Greene and Wuts, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc., Interscience, 2nd edition, New York) known to those of ordinary skill in the art. Presently preferred protecting groups include methyl and benzyl for the hydroxyl moiety, and trifluoroacetamide and benzyl for the amino moiety.
In each of the general reaction schemes discussed or illustrated above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres (xcx9c50,000 Pa) to about 5 atmospheres (xcx9c500,000 Pa) are generally acceptable, and ambient pressure, i.e. about 1 atmosphere (xcx9c100,000 Pa), is preferred as a matter of convenience.
The compounds of this invention may be prepared in racemic form and be resolved into their component enantiomers by standard techniques such as fractional crystallization or preparative chromatography. Alternatively, enantiomers of the invention compounds may be synthesized from the appropriate optically active intermediates or starting materials using any of the general processes described herein.
Further, optically active compounds of this invention may be prepared using enantioselective reactions or by resolution techniques such as the preparation of diastereomers by reacting the racemic material with an optically active reagent.
The compounds of this invention are valuable estrogen agonists or antagonists, and thus valuable pharmaceutical agents. Those that are estrogen agonists are useful for oral contraception, relief of the symptoms of menopause, prevention of threatened or habitual abortion, relief of dysmenorrhea, relief of dysfunctional uterine bleeding, relief of endometriosis, an aid in ovarian development, treatment of acne, diminution of excessive growth of body hair in women (hirsutism), the prevention and/or treatment of cardiovascular disease, prevention and treatment of atherosclerosis, prevention and treatment of osteoporosis, treatment of benign prostatic hyperplasia and prostatic carcinoma, obesity, and suppression of post-partum lactation. These agents also have a beneficial effect on plasma lipid levels and as such are useful in treating and/or preventing hypercholesterolemia.
While the compounds of this invention are typically estrogen agonists in bone, unexpectedly they are also often antiestrogens in breast tissue and as such would be useful in the treatment and prevention of breast cancer.
While the compounds of this invention are expected to be sufficiently active if administered separately, in many instances it will be beneficial to combine these compounds with other compounds in order to even more effectively treat a disease or condition. Exemplary categories of compounds which will be beneficial in combination with the compounds of the present invention include an anabolic agent, a prodrug thereof, or a pharmaceutically acceptable salt of said anabolic agent or said prodrug; a growth hormone or a growth hormone secretagogue, a prodrug thereof, or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug; a prostaglandin agonist/antagonist, a prodrug thereof, or a pharmaceutically acceptable salt of said prostaglandin agonist/antagonist or said prodrug; or a parathyroid hormone or sodium fluoride.
It will also be useful to present the compounds of the present invention in the form of kits useful for treating or preventing a disease, disorder, condition, or symptom mediated by an estrogen receptor and/or caused by lowered estrogen levels, said kit comprising a compound of the present invention and a pharmaceutically acceptable vehicle, carrier, or diluent in a dosage form, and a container for containing said dosage form.
In many instances, it will be preferable for the kit to include, in addition to a compound of the present invention, an anabolic agent, a prodrug thereof, or a pharmaceutically acceptable salt of said anabolic agent or said prodrug; a growth hormone or a growth hormone secretagogue, a prodrug thereof, or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug; a prostaglandin agonist/antagonist, a prodrug thereof, or a pharmaceutically acceptable salt of said prostaglandin agonist/antagonist or said prodrug; or a parathyroid hormone or sodium fluoride.
Methods for Testing the Activity of Invention Compounds
Assay 1: Control and Prevention of Endometriosis
A preferred protocol for surgically inducing endometriosis is that described by Jones, Acta Endoerinol (Copenh), 106:282-88 (1984). Adult Charles River Sprague-Dawley CD(copyright) female rats (200-240 g) are used. An oblique ventral incision is made through the skin and musculature of the body wall. A segment of the right uterine horn is excised, the myometrium is separated from the endometrium, and the segment is cut longitudinally. A 5xc3x975 mm section of the endometrium, with the epithelial lining apposed to the body wall, is sutured at its four corners to the muscle using polyester braid (Ethiflex, 7-0(copyright)). The criterion of a viable graft is the accumulation of fluid similar to that which occurs in the uterus as a result of estrogen stimulation.
Three weeks after transplantation of the endometrial tissue (+3 weeks) the animals are laparotomized, the volume of the explant (lengthxc3x97widthxc3x97height) in mm is measured with calipers, and treatment is begun. The animals are injected sc for 3 weeks with 10 to 1000 mg/kg/day of a test compound according to the present invention. Control animals bearing endometrial explants are injected sc with 0.1 ml/day of corn oil for 3 weeks. At the end of the 3 week treatment period (+6 weeks), the animals are laparotomized and the volume of the explant determined. Eight weeks after cessation of treatment (+14 weeks) the animals are sacrificed and the explants are measured again. Statistical analysis of the explant volume is by an analysis of variance.
Assay 2: Effect on Prostate Weight
Three-month-old male Sprague-Dawley rats are administered by subcutaneous injection control vehicle (10% ethanol in water), estradiol (30 xcexcg/kg), testosterone (1 mg/kg), or a test compound according to the present invention daily for 14 days (n=6/group). After 14 days the animals are sacrificed, the prostate is removed, and the wet prostate weight is determined. Mean weight is determined and statistical significance (p less than 0.05) is determined compared to the vehicle-treated group using the Student""s t-test.
Active compounds significantly (P less than 0.05) decrease prostate weight compared to controls. Testosterone is expected to have no effect while estrogen at 30 xcexcg/kg is expected to significantly reduce prostate weight.
Assay 3: In Vitro Estrogen Receptor Binding
An in vitro estrogen receptor binding assay that measures the ability of the compounds of the present invention to displace [3H]-estradiol from human estrogen receptor obtained by recombinant methods in yeast, bacteria, or mammalian cells is used to determine the estrogen receptor binding affinity of the compounds of this invention. The materials used in this assay are: (1) TD-0.3 assay buffer (containing 10 mM Tris, pH 7.6, 0.3 M potassium chloride, and 5 mM DTT); (2) the radioligand used is [3H]-estradiol obtained from New England Nuclear (Boston, Mass.); (3) the cold ligand used is estradiol obtained from Sigma (St. Louis, Mo.); and (4) recombinant human estrogen receptor, hER.
A solution of the compound being tested is prepared in TD-0.3 with 4% DMSO and 16% ethanol. The tritiated estradiol is dissolved in TD-0.3 such that the final concentration in the assay is 5 nM. The hER is also diluted with TD-0.3 such that 0.2 nM hER is in each assay well. Using microtiter plates, each incubate receives 50 xcexcl of cold estradiol (nonspecific binding) or the test compound solution, 20 xcexcl of the tritiated estradiol, and 30 xcexcl of hER solutions. Each plate contains varying concentrations of the compound and total binding controls in triplicate. The plates are incubated overnight at 4xc2x0 C. The binding reaction is then terminated by the addition and mixing of 100 ml of 3% hydroxylapatite in 10 mM Tris, pH 7.6, followed by incubation for 15 minutes at 4xc2x0 C. The mixture is centrifuged and the pellet washed four times with 1% Triton-X100 in 10 mM Tris, pH 7.6. The hydroxylapatite pellets are suspended in Ecolite (+) (ICN Biomedicals, Inc., Aurora, Ohio) and radioactivity is assessed using beta scintigraphy. The mean of all triplicate data points (counts per minute, cpm""s) is determined. Specific binding is calculated by subtracting nonspecific cpm""s (defined as counts that remain following separation of reaction mixture containing recombinant receptor, radioligand, and excess unlabeled ligand) from total bound cpm""s (defined as counts that remain following the separation of reaction mixture containing only recombinant receptor, radioligand). Test compound potency is determined by means of IC50 determinations (the concentration of a test compound needed to inhibit 50% of the of the total specific tritiated estradiol bound). Specific binding in the presence of varying concentrations of test compound is determined and calculated as percent specific binding of total specific radioligand bound. Data are plotted as percent inhibition by test compound (linear scale) versus test compound concentration (log scale).
Assay 4: Effect on Total Cholesterol Levels
The effect of the compounds of the present invention on plasma levels of total cholesterol is measured as follows. Blood samples are collected via cardiac puncture from anesthetized female (Sprague-Dawley) rats 4-6 months of age that are bilaterally ovariectomized and treated with the test compound (10-1000 xcexcg/kg/day, for example, sc or orally for 28 days or with control vehicle for the same time), or sham operated. The blood is placed in a tube containing 30 xcexcl of 5% EDTA (10 xcexcl EDTA/1 ml of blood). After centrifugation at 2500 rpm for 10 minutes at 20xc2x0 C. the plasma is removed and stored at xe2x88x9220xc2x0 C. The total cholesterol is assayed using a standard enzymatic determination kit from Sigma Diagnostics (Procedure No. 352).
Assay 5: Effect on Obesity
Ten-month-old female Sprague-Dawley rats, weighing approximately 450 grams, are sham-operated or ovariectomized and treated orally with vehicle, 17xcex1-ethynyl-estradiol at 30 mg/kg/day, or a compound according to the present invention at 10-1000 mg/kg/day for 8 weeks. There are 6 to 7 rats in each sub group. On the last day of the study, body composition of all rats is determined via dual energy x-ray absorptiometry using a Hologic QDR-1000/W (Hologic, Bedford, Mass.) equipped with whole body scan software that shows the proportions of fat body mass and lean body mass.
A decrease in fat body mass indicates that the test compound is useful in preventing and treating obesity.
Abbreviations used in the following examples and preparations include:
1,2 DCE 1,2-Dichloroethane
d Doublet
dd Double Doublet
DMAP 4-Dimethylamino Pyridine
EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride
EtOAc Ethyl Acetate
EtOH Ethyl Alcohol or Ethanol
Et2O Ethyl Ether
Et3N Triethylamine
HOBt 1-Hydroxybenzotriazole
HPLC High Pressure Liquid Chromatography
hr Hour(s)
m Multiplet
MeOH Methyl Alcohol or Methanol
min Minute(s)
MS Mass Spectrometry
NMR Nuclear Magnetic Resonance
PPAA 1-Propanephosphonic Acid Cyclic Anhydride
q Quartet
RT (or rt) room temperature (about 20-25xc2x0 C.)
s Singlet
sat. Saturated
t Triplet
TBAF Tetrabutyl Ammonium Fluoride
TFA Trifluoroacetic Acid
THF Tetrahydrofuran